Project Summary The development of novel medications with robust effect sizes and good safety and tolerability is an INIA RFA research priority. This translational project will respond to this research challenge by providing proof-of-concept human laboratory testing of the top three neuroimmune drug candidates identified as having therapeutic potential for alcohol use disorder by Dr. Mayfield/Farris/Ponomarev's ?drugging the network? computational genomic analyses and by Drs. Bell's, Blednov/Messing's, Crabbe/Ozburn's and Lasek's animal models. Drugs identified for human study will either be FDA-approved for other indications or available for study under an IND and will be selected by Dr. Mason based on scientific prioritization by the INIA-Neuroimmune Executive Committee and safety considerations. Drugs will be tested in a highly standardized, reliable, and valid human laboratory model informing the three stages of the addiction cycle: withdrawal/negative affect, preoccupation/anticipation, and binge/intoxication, with human laboratory results serving as an analogue for drinking outcomes of double-blind, placebo-controlled clinical trials. Subjects for each study will be 50 non- treatment-seeking male and female paid volunteers who meet DSM-5 criteria for alcohol use disorder of ? moderate severity (AUD-MS). Studies are randomized, double-blind, and placebo-controlled. The treatment duration is at least 1-week and guided by drug pharmacokinetics. The primary endpoint is craving scores in response to in vivo alcohol cues presented in the laboratory, with confirmatory physiological outcomes, and naturalistic measures of drinking, mood, and craving. Specific Aim 1: To evaluate INIA-Neuroimmune drug candidates in paid non-treatment-seeking volunteers with current AUD-MS using the human lab model informing targets for the 3 stages of the addiction cycle. Specific Aim 2: To identify potential biomarkers of clinical outcomes in peripheral markers of stress and inflammation (e.g., high-sensitivity C-reactive protein, selected chemokines, pro- and antiinflammatory cytokines, and cortisol) in collaboration with Drs. Roberto/Roberts/Bajo. Safety Aim: To evaluate the safety and tolerability of INIA-Neuroimmune drug candidates in subjects with AUD-MS, as assessed by significant changes from baseline in EKG, routine blood and urine biochemistry, vital signs, physical exam, and subjective complaints relative to placebo. Hypothesis: The overall hypothesis under test in that, relative to placebo, novel drug candidates identified by INIA- Neuroimmune will significantly attenuate responsivity to alcohol cues in the human lab model and reduce drinking, craving, and negative affect during treatment and 1-month of post-treatment follow-up. Interpretation of Results: Positive findings will provide clinical validation of neuroimmune targets and mechanisms identified by INIA-Neuroimmune and provide a rational basis for later phase testing of candidate drugs as potential therapeutics for AUD-MS.